The Use of Immunotherapy in Blood Cancer Treatment
Lee Greenberger, chief scientific officer at the Leukemia and Lymphoma Society, discusses the use of immunotherapy in blood cancer treatment.
BY Kristie L. Kahl and Lee Greenberger
PUBLISHED February 14, 2020
Kristie L. Kahl: Can you give us a background on what immunotherapy is and how it works?
Lee Greenberger: Immunotherapy has a long history in blood cancer. It goes all the way back to transplantations where you take the immune cells from one patient and put it into the other. It actually can end up being curative in that transplant situation. We now know the molecular basis of that, and immunotherapy has evolved considerably, specifically in the last 10 years where we have sort of brought it out of the lab and now moving it forward.
The story begins with monoclonal antibodies and (Rituxan [rituximab]), which is a monoclonal antibody to CD20, which sits on the surface of tumor cells. It was one of the first antibodies approved, along with (Herceptin [trastuzumab]) for breast cancer. Rituxan is used for blood cancers and used widely. So, the concept that you can make antibodies in the laboratory, manufacture them, bring them out to patients and it has shown that it is highly effective in multiple lymphomas. Since that time, there are multiple antibodies that have come out.
Beyond that, in the last 10 years in particular, we now know that there are all sorts of mechanisms control the immune system, and in fact, the immune system is highly effective at getting rid of tumor cells. For example, in the late 1980’s, there was an investigator in Israel who figured out how to actually manufacture from scratch, a gene and put it into T cells, which would allow the T cells, which are part of the immune system, to home on the tumor cells and kill those cells. That evolved into something called chimeric antigen receptor-therapy, or CAR-T. CAR-T has gone through multiple evolutions, but there are now two CAR-T products on the market, and basically what this is a genetic engineering of the T cells.
You take the T cells out of the patient, genetically engineer that gene, put it into those T cells, and now that T cell can home on the tumor cell. When it arrives at the tumor cell, it is recognizing something very specific on those tumor cells. It will dramatically expand. So, instead of having one T cell, now you’ll have a million cells. And those cells can very effectively kill tumor cells for certain patients. For example, it’s been used very effectively in children with B-cell type leukemia. It’s also used in certain types of lymphoma, most notably diffuse large B cell lymphoma and recently mantle cell lymphoma.
So, that’s one type. The cells have to come out of the patient. Manufacturing takes about 14-21 days, and put back into the patient. That can be a very effective solution for treating patients with relapsed disease.
Along with CAR-T cell therapy, there is bi-specific antibodies. These are antibodies that are capable of taking the T cells of the patient and making them recognize the tumor cells. So, instead of a linker that will move these cells together, hence the notion of bi-specific: one to the tumor cells, one to the T cells, bring them together and it makes the T cells capable of killing the tumor cells.
You also have antibody drug conjugates. In that case, you take an antibody which is going to home in on the surface of the tumor cells, and you link it to a toxin. This technology is actually quite fascinating because it actually grew up about the same time that monoclonal antibodies were developed. We had a bunch of super toxins discovered from products. They were so toxic they couldn’t even be used by themselves, but if you take that toxin and link it to an antibody, now you have a guided missile. The antibody arrives at the tumor cell, brings the toxin into the tumor cell. Antibody drug conjugates have been on the market since the late 1990’s.
Bottom line is, the reason why immunotherapy is so attractive is because it specifically homes on the tumor cell, it’s highly effective at killing the tumor cell, and it doesn’t have some of the harsh, toxic side effects that cytotoxic drugs typically do. That’s not to say they are devoid of toxicity, but it’s of a different nature and it in general can be managed well.
Kristie L. Kahl: What are some of the more notable side effects?
Lee Greenberger: For CAR-T cell therapy, which is among the most advanced, you get something called cytokine release syndrome. These T cells basically become so revved up, that they secrete a lot of cytokine products that can make you feel ill, cause fever, and in rare cases can be lethal if you can’t control them. So, they can compromise organs. Physicians nowadays with CAR-T cell therapy are well aware of some of these cytokine release syndrome (symptoms). They tend to appear a few days after therapy, and don’t last for very long but you have to recognize that they’re there. It’s a very common event for CAR-T cell therapy. We’re getting better at these things. They used to be grade 3, which is serious, now some of the new CAR-T cell therapies are having low-grade (side effects), which do not require observation.
Neurotoxicity is another, where the patient may be disoriented. This also comes up as the T cell numbers increase dramatically, the neurotoxicity could manifest as confusion, disorientation, and then it will die away over time, generally over a couple of weeks.
So, those are two things to watch out for for CAR-T cell therapy. They’re manageable, but it can be of a serious nature.
Kristie L. Kahl: How does the multidisciplinary approach play a role?
Lee Greenberger: CAR-T cell therapy requires the involvement of many people in the treatment. There are cells that have to come out of the patient, where you take the blood out of the patient and harvest the cells, so there are technicians involved harvesting the cells. Then they go out to a laboratory, and they will make them in their labs. The cells go back into the patient, and that requires careful observation, typically for the next week after you get these cells. This can require an in-hospital stay or outpatient. It requires a physician overseeing it, nurses who are qualified to recognize some of the early symptoms, careful monitoring. We can monitor these things because we know we have biomarkers to know how aggressive these T cells are expanding. So, for example, for cytokine release syndrome, IL6 levels can shoot way high. So, if you are analyzing the blood, and can get these results back quickly, we now have therapies to knock down the IL6 levels and block those effects.
Kristie L. Kahl: What are some questions patients can ask their doctors so that they can become better informed about their treatment decisions?
Lee Greenberger: The road to treating these blood cancers is actually a long, involved road. In some cases, some blood cancers require watch-and-wait and we don’t do anything. In other cases, a newly diagnosed patient will begin to get treatment, which depends on (the type of blood cancer). The treatments are all quite different. In some of those cases, the initial treatment will keep the patient in check for years. Don’t forget that many of these blood cancers happen in older patients (60-70 years old). So, if you can keep the disease in check for 20 years, you’re doing fine. In other cases, these lymphomas will come back. Even with CAR-T therapy, where we can control the disease long-term as best as we can, we can expect that a certain number of these patients, the disease will return. So, with relapsed or refractory disease, these are the ones that are going to require additional treatments.